Methods and compositions for treating ocular disorders

ABSTRACT

The present invention provides a method for treating and/or preventing damage to a retina or optic nerve in a subject comprising administering to the subject a therapeutically effective amount of oncomodulin. Preferably, the subject is a mammal, most preferably, a human. In preferred embodiments, the oncomodulin may be used in combination with mannose, a mannose derivative and/or inosine.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit under 35 U.S.C §119(e) of U.S.provisional Application No. 60/332,719, filed Nov. 14, 2001 and is aContinuation-In-Part of application Ser. No. 09/872,347, filed Jun. 1,2001, which claims the benefit under 35 U.S.C §119(e) of U.S.Provisional Application No. 60/208,778, filed Jun. 1, 2000.

BACKGROUND OF THE INVENTION

In the United States, glaucoma is the second leading cause of legalblindness overall and the leading cause of blindness in African-Americanindividuals (Hiller, R and H. A. Kahn, (1975) Am. J. Ophthalmol 80: 62and Kahn, H. A. and H. B. Moorhead (1973) US Public Health ServicePublication NIH73-427, 120). Primary open glaucoma (POAG) is the mostcommon form of glaucoma affecting 1-2% of the population over age forty(J. M. Tielsch et al., (1990) Arch Ophthalmol. 108: 286). Nearly 12,000people in the United States are blinded annually by this disorder (H. B.Moorhead (1973) US Public Health Service Publication NIH73-427, 1202-4;J. M. Tielsch et al., (1990) Arch Ophthalmol. 108: 286 and J. M.Tielsch, in Transactions of the New Orleans Academy of Ophthalmology,Ball, S. F. Franklin R. M., Eds (Kugler, Amsterdam, 1993), pp61-68).

Glaucoma is a progressive disease which leads to optic nerve damage and,ultimately, total loss of vision. The causes of this disease have beenthe subject of extensive studies for many years, but are still not fullyunderstood. The principal symptom of and/or risk factor for the diseaseis elevated intraocular pressure or ocular hypertension due to excessaqueous humor in the anterior chamber of the eye.

The causes of aqueous humor accumulation in the aniterior chamber arenot fully understood. It is known that elevated intraocular pressure(“IOP”) can be at least partially controlled by administering drugswhich either reduce the production of aqueous humor within the eye, suchas beta-blockers and carbonic anhydrase inhibitors, or increase theoutflow of aqueous humor from the eye, such as miotics andsympathomimetics.

Most types of drugs conventionally used to treat glaucoma havepotentially serious side effects. Miotics such as pilocarpine can causeblurring of vision and other visual side effects, which may lead eitherto decreased patient compliance or to termination of therapy.Systemically administered carbonic anhydrase inhibitors can also causeserious side effects such as nausea, dyspepsia, fatigue, and metabolicacidosis, which side effects can affect patient compliance and/ornecessitate the termination of treatment. Another type of drug,beta-blockers, have increasingly become associated with seriouspulmonary side effects attributable to their effects on beta-2 receptorsin pulmonary tissue. Sympathomimetics, on the other hand, may causetachycardia, arrhythmia and hypertension. Recently, certainprostaglandins and prostaglandin derivatives have been described in theart as being useful in reducing intraocular pressure.

While normalization of intraocular pressure can prevent further loss ofsight, it cannot alone restore vision that has already been lost. Thenerve cells that generate or constitute the optic nerve do, however,retain the natural ability to regenerate the axons (connecting fibers)that populate the optic nerve provided the proper growth factor ispresent. There is therefore a continuing need for therapies that inducethe regeneration of optic nerve fibers that have been lost therebyfacilitating restoration of sight.

SUMMARY OF THE INVENTION

The present invention provides methods and composition for preventingand/or treating damage to the retina and optic nerve, including damageresulting from ischemic or hypoxic stress, excess intraocular pressure,or injury. The composition can be used specifically to treat damageassociated with vascular occlusion or anterior ischemic opticneuropathy. The composition is also useful for treating damage arisingfrom the presence of cytotoxins or neurotoxins, such as glutamate orother excitatory amino acids or peptides, excess intracellular calcium,and free radicals. In particular, the composition can be useful intreating damage associated with branch and central vein/arteryocclusion, trauma, edema, angle-closure glaucoma, open-angle glaucoma,age related macular degeneration, retinitis pigmentosa, retinaldetachments, damage associated with laser therapy (includingphotodynamic therapy), and surgical light-induced iatrogenicretinopathy.

In one embodiment, the present invention provides a method for treatingand/or preventing damage to a retina or optic nerve in a subjectcomprising administering to the subject a therapeutically effectiveamount of a macrophage-derived factor or neurotrophic factor. Preferredneurotrophic factors include, for example, oncomodulin and TGF-β.Oncomodulin is most preferred. Preferably, the subject is a mammal, mostpreferably, a human.

In certain embodiments, the damage to the optic nerve is the result ofglaucoma. In other embodiments, the damage to the retina is the resultof macular degeneration.

In one embodiment, a cAMP modulator and/or an axogenic factor is furtheradministered to the subject. The components can be used separately, butadministered contemporaneously. While not wishing to be bound by aparticular theory, it is believed that the cAMP modulator and axogenicfactor potentiates the activity of the neurotrophic factor.

Preferably, the cAMP modulator is non-hydrolyzable cAMP analogues,forskolin, adenylate cyclase activators, macrophage-derived factors thatstimulate cAMP, macrophage activators, calcium ionophores, membranedepolarization, phosphodiesterase inhibitors, specific phosphodiesteraseIV inhibitors, beta2-adrenoreceptor inhibitors or vasoactive intestinalpeptide.

Preferred axogenic factors include mannose (sometimes referred to as“AF-1”), mannose derivatives and inosine.

The neurotrophic factor may be administered, for example, topically tothe eye of the subject or by intraocular injection.

The present invention further provides an article of manufacturecomprising packaging material and a pharmaceutical agent containedwithin said packaging material, wherein said packaging materialcomprises a label which indicates said pharmaceutical may beadministered, for a sufficient term at an effective dose, for treatingand/or preventing damage to a retina or optic nerve together with apharmaceutically acceptable carrier, wherein the pharmaceutical agentcomprises oncomodulin.

Finally, the present invention provides a pharmaceutical kit for thetreatment and/or prevention of damage to a retina or optic nerve. Thekit includes the combination of:

-   -   (a) an oncomodulin;    -   (b) inosine and/or mannose (or mannose derivative); and    -   (c) a cAMP modulator.

Other aspects of the invention are disclosed infra.

DETAILED DESCRIPTION

The present invention provides methods and composition for preventingand/or treating damage to the retina and optic nerve, including damageresulting from ischemic or hypoxic stress, excess intraocular pressure,or injury. The composition can be used specifically to treat damageassociated with vascular occlusion or anterior ischemic opticneuropathy. The composition is also useful for treating damage arisingfrom the presence of cytotoxins or neurotoxins, such as glutamate orother excitatory amino acids or peptides, excess intracellular calcium,and free radicals. In particular, the composition can be useful intreating damage associated with branch and central vein/arteryocclusion, trauma, edema, angle-closure glaucoma, open-angle glaucoma,age related macular degeneration, retinitis pigmentosa, retinaldetachments, damage associated with laser therapy (includingphotodynamic therapy), and surgical light-induced iatrogenicretinopathy.

The composition of the present invention includes a macrophage-derivedfactor.

As used herein, the term “macrophage-derived factor” includes any factorderived from a macrophage that has the ability to produce aneurosalutary effect in a subject. Macrophage-derived factors include,but are not limited to, peptides such as oncomodulin and TGF-β. See, WO01/091783, the disclosure of which is incorporated herein by reference.

As used herein, a “neurosalutary effect” means a response or resultfavorable to the health or function of a neuron, of a part of thenervous system, or of the nervous system generally. Examples of sucheffects include improvements in the ability of a neuron or portion ofthe nervous system to resist insult, to regenerate, to maintaindesirable function, to grow or to survive. The phrase “producing aneurosalutary effect” includes producing or effecting such a response orimprovement in function or resilience within a component of the nervoussystem. For example, examples of producing a neurosalutary effect wouldinclude stimulating axonal outgrowth after injury to a neuron; renderinga neuron resistant to apoptosis; rendering a neuron resistant to a toxiccompound such as β-amyloid, ammonia, or other neurotoxins; reversingage-related neuronal atrophy or loss of function; or reversingage-related loss of cholinergic innervation.

As used herein, a “neurotrophic factor” or “neurotrophic compound” isone that induces a “neurosalutary effect” as defined above. Examples ofpreferred neurotrophic compounds include oncomodulin and TGF-β.Oncomodulin is preferred.

The term “axogenic factor” includes any factor that has the ability tostimulate axonal regeneration from a neuron. Examples of axogenicfactors include AF-1 (mannose) and AF-2 as described in, for example,Schwalb et al. (1996) Neuroscience 72(4):901-10; Schwalb et al., id.;and U.S. Pat. No. 5,898,066, the contents of which are incorporatedherein by reference. Other examples of axogenic factors include purines,such as inosine, as described in, for example, PCT application No.PCT/US98/03001, U.S. Pat. No. 6,440,455 and Benowitz et al. (1999) Proc.Natl. Acad. Sci. 96(23):13486-90, the contents of which are incorporatedherein by reference.

A preferred axogenic factor in mannose(e.g., D-mannose or L-mannose) ora mannose derivative, e.g., aminomannose, mannose-6-phosphate (Phosporicacid mano-(3,4,5,6-tetrahydroxy-tetrahydro-pyran-2-ylmethy) ester).

A therapeutically effective amount or dosage of an axogenic factor mayrange from about 0.001 to 30 mg/kg body weight, with other ranges of theinvention including about 0.01 to 25 mg/kg body weight, about 0.1 to 20mg/kg body weight, about 1 to 10 mg/kg, 2 to 9 mg/kg, 3 to 8 mg/kg, 4 to7 mg/kg, and 5 to 6 mg/kg body weight. For inosine, a non-limiting rangefor a therapeutically effective in vivo concentration in tissuecontaining the injury is 5 μM to 5 mM.

The term “cAMP modulator” includes any compound which has the ability tomodulate the amount, production, concentration, activity or stability ofcAMP in a cell, or to modulate the pharmacological activity of cellularcAMP. cAMP modulators may act at the level of adenylate cyclase,upstream of adenylate cyclase, or downstream of adenylate cyclase, suchas at the level of cAMP itself, in the signaling pathway that leads tothe production of cAMP. Cyclic AMP modulators may act inside the cell,for example at the level of a G-protein such as Gi, Go, Gq, Gs and Gt,or outside the cell, such as at the level of an extra-cellular receptorsuch as a G-protein coupled receptor. Cyclic AMP modulators includeactivators of adenylate cyclase such as forskolin; non-hydrolyzableanalogues of cAMP including 8-bromo-cAMP, 8-chloro-cAMP, or dibutyrylcAMP (db-cAMP); isoprotenol; vasoactive intestinal peptide; calciumionophores; membrane depolarization; macrophage-derived factors thatstimulate cAMP; agents that stimulate macrophage activation such aszymosan or IFN-γ; phosphodiesterase inhibitors such as pentoxifyllineand theophylline; specific phosphodiesterase IV (PDE IV) inhibitors; andbeta 2-adrenoreceptor agonists such as salbutamol. The term cAMPmodulator also includes compounds which inhibit cAMP production,function, activity or stability, such as phosphodiesterases, such ascyclic nucleotide phosphodiesterase 3B. cAMP modulators which inhibitcAMP production, function, activity or stability are known in the artand are described in, for example, Nano et al. (2000) Pflugers Arch439(5):547-54, the contents of which are incorporated herein byreference.

“Phosphodiesterase IV inhibitor” refers to an agent that inhibits theactivity of the enzyme phosphodiesterase IV. Examples ofphosphodiesterase IV inhibitors are known in the art and include4-arylpyrrolidinones, such as rolipram, nitraquazone, denbufylline,tibenelast,CP-80633 and quinazolinediones such as CP-77059.

“Beta-2 adrenoreceptor agonist” refers to an agent that stimulates thebeta-2 adrenergic receptor. Examples of beta-2 adrenoreceptor agonistsare known in the art and include salmeterol, fenoterol andisoproterenol.

The term “administering” to a subject includes dispensing, delivering orapplying an active compound in a pharmaceutical formulation to a subjectby any suitable route for delivery of the active compound to the desiredlocation in the subject, including delivery by either the parenteral ororal route, intramuscular injection, subcutaneous/intradermal injection,intravenous injection, buccal administration, transdermal delivery andadministration by the rectal, colonic, vaginal, intranasal orrespiratory tract route.

As used herein, the language “contacting” is intended to include both invivo or in vitro methods of bringing a compound of the invention intoproximity with a neuron such that the compound can exert a neurosalutaryeffect on the neuron.

As used herein, the term “effective amount” includes an amounteffective, at dosages and for periods of time necessary, to achieve thedesired result, such as sufficient to produce a neurosalutary effect ina subject. An effective amount of an active compound as defined hereinmay vary according to factors such as the disease state, age, and weightof the subject, and the ability of the active compound to elicit adesired response in the subject. Dosage regimens may be adjusted toprovide the optimum therapeutic response. An effective amount is alsoone in which any toxic or detrimental effects of the active compound areoutweighed by the therapeutically beneficial effects.

The term “subject” is intended to include animals. In particularembodiments, the subject is a mammal, a human or nonhuman primate, adog, a cat, a horse, a cow or a rodent.

The route of administration and the dosage regimen will be determined byskilled clinicians, based on factors such as the exact nature of thecondition being treated, the severity of the condition, and the age andgeneral physical condition of the patient. Specific routes ofadministration may include topical application (such as by eyedrops,creams or erodible formulations to be placed under the eyelid),intraocular injection into the aqueous or the vitreous humor, injectioninto the external layers of the eye, such as via subconjunctivalinjection or subtenon injection, parenteral administration or via oralroutes.

The neurotrophic compound may be contained in various types ofpharmaceutical compositions, in accordance with formulation techniquesknown to those skilled in the art. For example, the compounds may beincluded in tablets, capsules, solutions, suspensions, and other dosageforms adapted for oral administration; solutions and suspensions adaptedfor parenteral use; and solutions and suspensions adapted for topicalophthalmic, depot, or intra-ocular injection. Solutions, suspensions,and other dosage forms adapted for depot or intra-ocular injection areparticularly preferred for the prevention or treatment of acute orchronic retinal or optic nerve head damage. Compositions can also bedelivered according to the teachings in WO 96/05840, which isincorporated herein by reference.

The present invention is particularly directed to compositions adaptedfor treatment of retinal and optic nerve head tissues. The ophthalmiccompositions of the present invention will include one or moreneurotrophic compounds and a pharmaceutically acceptable vehicle. Anaxogenic factor and/or a cAMP modulator may also be included in thecomposition. Various types of vehicles may be used. The vehicles willgenerally be aqueous in nature. Aqueous solutions are generallypreferred based on ease of formulation as well as a patient's ability toeasily administer such compositions by means of instilling one to twodrops of the solutions in the affected eyes. However, the neurotrophiccompounds of the present invention may also be readily incorporated intoother types of compositions, such as suspensions, viscous orsemi-viscous gels, or other types of solid or semi-solid compositions.Suspensions may be preferred for neurotrophic compounds that arerelatively insoluble in water. The ophthalmic compositions of thepresent invention may also include various other ingredients, such asbuffers, preservatives, co-solvents, and viscosity building agents.

An appropriate buffer system (e.g., sodium phosphate, sodium acetate orsodium borate) may be added to prevent pH drift under storageconditions.

Ophthalmic products for topical use may be packaged in multidose form.Preservatives are thus required to prevent microbial contaminationduring use. Suitable preservatives include: benzalkonium chloride,thimerosal, chlorobutanol, methyl paraben, propyl paraben, phenylethylalcohol, edetate disodium, sorbic acid, polyquatemium-1, or other agentsknown to those skilled in the art. Such preservatives are typicallyemployed at a level of from 0.001 to 1.0% weight/volume (“% w/v”). Suchpreparations may be packaged in dropper bottles or tubes suitable forsafe administration to the eye, along with instructions for use.

When the ophthalmic compositions of the present invention areadministered during intraocular surgical procedures, such as throughretrobulbar or periocular injection and intraocular perfusion orinjection, the use of balanced salt irrigating solutions as vehicles aremost preferred. BSS Sterile Irrigating Solution and BSS Plus® SterileIntraocular Irrigating Solution (Alcon Laboratories, Inc., Fort Worth,Tex. USA) are examples of physiologically balanced intraocularirrigating solutions. The latter type of solution is described in U.S.Pat. No. 4,550,022 (Garabedian, et al.), the entire contents of whichare hereby incorporated in the present specification by reference.Retrobulbar and periocular injections are known to those skilled in theart and are described in numerous publications including, for example,Ophthalmic Surgery: Principles of Practice, Ed., G. L. Spaeth. W. B.Sanders Co., Philadelphia, Pa., U.S.A., (1990).

As indicated above, use of the ophthalmic compositions of the presentinvention to prevent or reduce damage to retinal and optic nerve headtissues, as well as to enhance functional recovery after damage toocular tissues, is a particularly important aspect of the presentinvention. Ophthalmic conditions that may be treated include, but arenot limited to, retinopathies (including diabetic retinopathy andretrolental fibroplasia), macular degeneration, ocular ischemia,glaucoma. Other conditions to be treated with the methods of theinvention include damage associated with injuries to ophthalmic tissues,such as ischemia reperfusion injuries, photochemical injuries, andinjuries associated with ocular surgery, particularly injuries to theretina or optic nerve head by exposure to light or surgical instruments.The ophthalmic compositions may also be used as an adjunct to ophthalmicsurgery, such as by vitreal or subconjunctival injection followingophthalmic surgery. The compounds may be used for acute treatment oftemporary conditions, or may be administered chronically, especially inthe case of degenerative disease. The ophthalmic compositions may alsobe used prophylactically, especially prior to ocular surgery ornoninvasive ophthalmic procedures or other types of surgery.

In general, the doses used for the above described purposes will vary,but will be in an effective amount to prevent, reduce or ameliorateretinal or optic nerve head tissue damage resulting from any of theabove listed conditions. As used herein, the term “pharmaceuticallyeffective amount” refers to an amount of one or more neurotrophiccompounds such that treatment of a patient with that amount can beassociated with a medically desirable change in ocular function, or thatcan prevent, reduce, or ameliorate chronic or acute retinal or opticnerve damage resulting from conditions such as trauma to the eye,ischemia or hypoxia.

The doses used for any of the above-described purposes of theneurotrophic factor will generally be from about 0.01 to about 100milligrams per kilogram of body weight (mg/kg), administered one to fourtimes per day. When the compositions are dosed topically, they willgenerally be in a concentration range of from 0.001 to about 5% w/v,with 1-2 drops administered 1-4 times per day.

There is also provided an article of manufacture comprising packagingmaterial and a pharmaceutical agent contained within the packagingmaterial. The packaging material comprises a label which indicates thatthe pharmaceutical may be administered, for a sufficient term at aneffective dose, for treating and/or preventing damage to the retina andoptic nerve, including damage resulting from ischemic or hypoxic stress,excess intraocular pressure, or injury, especially damage resulting fromglaucoma and macular degeneration. The pharmaceutical agent comprisesneurotrophic compounds of the present invention together with apharmaceutically acceptable carrier.

As used herein, the term “pharmaceutically acceptable carrier” refers toany formulation which is safe, and provides the appropriate delivery forthe desired route of administration of an effective amount of at leastone compound of the present invention.

Pharmaceutical compositions (also referred to herein as “ophthalmiccompositions”) that include a neurotrophic factor and a pharmaceuticallyacceptable carrier may be packed with instructions for use of thepharmaceutical composition for treatment and/or prevention of damage tothe retina and optic nerve. In one embodiment, the pharmaceuticalcomposition may further include a cAMP modulator and/or an axogenicfactor, such as AF-1, AF-2 or a purine such as inosine. The ingredientsmay be packaged together in the form of a kit.

All of the components, e.g., neurotrophic factor, cAMP modulator andaxogenic factor, can be used separately, but administeredcontemporaneously, and can be given via a singular pharmaceuticallyacceptable dosage form for each component or combination of all thecomponents as an immediate release or controlled release dosage form.Contemporaneously means the three agents are administered separatelyover time, but have a combined effect together after their individualadministrations.

The invention is further illustrated by the following examples, whichshould not be construed as further limiting. The contents of allreferences, patents and published patent applications cited throughoutthis application are hereby incorporated by reference.

EXAMPLES

The following Examples 1 and 2 are formulations useful for intraocular,periocular or retrobulbar injection or perfusion.

Example 1

Component % w/v Oncomodulin 0.1 Dibasic sodium phosphate 0.2 HPMC 0.5Polysorbate 80  0.05 Benzalkonium chloride  0.01 Sodium chloride  0.75Edetate disodium  0.01 NaOH/HCl q.s. to pH 7.4 Purified water q.s. to100% Cremophor EL 10   Tromethamine  0.12 Boric acid 0.3 Mannitol 4.6Edetate disodium 0.1 Benzalkonium chloride 0.1 NaOH/HCl q.s. to pH 7.4Purified water q.s. to 100%

Example 2

Component % w/v Oncomodulin 0.1 Inosine 0.1 cAMP modulator 0.1 Dibasicsodium phosphate 0.2 HPMC 0.5 Polysorbate 80  0.05 Benzalkonium chloride 0.01 Sodium chloride  0.75 Edetate disodium  0.01 NaOH/HCl q.s. to pH7.4 Purified water q.s. to 100% Cremophor EL 10   Tromethamine  0.12Boric acid 0.3 Mannitol 4.6 Edetate disodium 0.1 Benzalkonium chloride0.1 NaOH/HCl q.s. to pH 7.4 Purified water q.s. to 100%

Example 3

A neurotrophic factor can be formulated in an ocular irrigating solutionused during ophthalmic surgery to treat retinal or optic nerve headdamage resulting from trauma due to injury or to prevent damagesresulting from the invasive nature of the surgery. The concentration ofthe neurotrophic compound in the irrigating solution will range from0.001 to 5% w/v.

A tablet formulation can be made pursuant to U.S. Pat. No. 5,049,586,incorporated herein by reference, and exemplified as following:.

Component % w/v Neurotrophic factor 60 Magnesium oxide 20 Corn starch 15Polyvinylpyrrolidone 3 Sodium carboxymethylcellulose 1 Magnesium sterate0.8

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments of the invention described herein. Such equivalents areintended to be encompassed by the following claims.

1. A method for treating damage to a retina or optic nerve in a subjectin need of such treatment comprising administering to the subject atherapeutically effective amount of oncomodulin.
 2. The method of claim1, further comprising administering to said subject a cAMP modulator. 3.The method of claim 2, wherein said cAMP modulator is non-hydrolyzablecAMP analogues, forskolin, adenylate cyclase activators,macrophage-derived factors that stimulate cAMP, macrophage activators,calcium ionophores, membrane depolarization, phosphodiesteraseinhibitors, specific phosphodiesterase IV inhibitors,beta2-adrenoreceptor inhibitors or vasoactive intestinal peptide.
 4. Themethod of claim 1, further comprising administering mannose or a mannosederivative to said subject.
 5. The method of claim 1, further comprisingadministering inosine to said subject.
 6. The method of claim 3, whereinthe cAMP modulator is forskolin.
 7. The method of claim 1, wherein thedamage to the optic nerve is the result of glaucoma.
 8. The method ofclaim 1, wherein the damage to the retina is the result of maculardegeneration.
 9. The method of claim 1, wherein the oncomodulin isadministered topically to the eye of the subject.
 10. The method ofclaim 1, wherein the oncomodulin is administered by intraocularinjection.
 11. The method of claim 1, wherein the oncomodulin isadministered to the subject in a pharmaceutically acceptableformulation.
 12. The method of claim 1, wherein the subject is a mammal.13. The method of claim 12, wherein the mammal is a human.